Active agents and their oligomers and polymers

ABSTRACT

Conjugates comprising at least two active agents linked by a diglycolic acid or polyglycol diacid linker are disclosed. The invention also concerns oligomers and polymers of these conjugates and their use in therapeutic and industrial applications for localized, immediate or fast release delivery of an active agent, such as an anti-microbial, anti-infective, or antiseptic agent.

RELATED APPLICATION

This application is a continuation of U.S. Ser. No. 12/441,347, filedMar. 13, 2009, and claims priority to International Application No.PCT/US2007/078426, filed Sep. 13, 2007 and claims priority under 35U.S.C. 119(e) to provisional application U.S. Ser. No. 60/825,465, filedSep. 13, 2006, which applications are incorporated herein by referencein their entireties.

This invention relates to conjugates comprising active agents linkedtogether by a diglycolic acid or polyglycol diacid linker, preferablyattached to the active agents at hydroxyl groups on the active agent.The invention also concerns oligomers and polymers of these conjugates.Optionally, the active agents may further contain one or more carboxylicacid groups, which are particularly useful as sites for polymerizationof the conjugates. The inventive conjugates and polymers release theiractive agents over a desirable period of time when applied to a desiredsite for use. Active agents include therapeutic agents and agents forindustrial applications, such as fungicides, pesticides, andanti-microbial agents, which can be applied to a desired surface forlocalized delivery of the active agent over a desired period of time.

BACKGROUND

Active agents, specifically therapeutic agents, conjugated tobiocompatible linkers and their use in forming the backbone of polymericdrug delivery systems are known. For example, U.S. Pat. No. 6,486,214 toUhrich discloses the tethering of two drug molecules via an aliphaticlinker and the subsequent polymerization of these compositions throughthe formation of anhydride linkages between the drug moieties. InUhrich, the moiety that connects the aliphatic linker to the drugmolecule is an amide, thioamide, ester or thioester group. Uhrichfurther discloses that these polyanhydrides may be used as vehicles forthe clinical delivery of the linked drug upon degradation of the polymerto its drug and biocompatible linker components.

Other aliphatic linkers have been disclosed in Australian Patent No.750,424 to Uhrich, U.S. App. Pub. No. 20050131199 A1 and U.S. App. Pub.No. 20050048121 A1. In addition to aliphatic linkers, AU 750,424discloses in general terms linkers with a backbone of an alkylene grouphaving one to twenty carbon atoms and linkers with a backbone of two totwenty carbon atoms having a structure selected from (—CH₂—CH₂—O—)_(m),(—CH₂—CH₂—CH₂—O—)_(m), and (—CH₂—CHCH₃—O—)_(m). In addition to aliphaticlinkers, U.S. App. Pub. Nos. 20050131199 A1 and 20050048121 A1 disclosein general terms linkers where one or more of the carbon atoms of thealiphatic chain linker are substituted with one or more oxygen ornitrogen atoms. The therapeutic agent-linker conjugates of theseapplications are used as monomers to form oligomeric and polymeric drugdelivery compositions.

U.S. Pat. No. 5,840,900 to Greenwald et al. discloses the use of asubstantially non-antigenic polymer as a linker to form a drug-linkerprodrug. The backbones of these linkers are polyalkylene oxidederivatives, preferably polyethylene glycol derivatives having amolecular weight above 20,000 Daltons. Further polymerization of theseconjugates is not taught.

U.S. App. Pub. No. 20050048121 A1 discloses copolymers ofaliphatically-linked diflunisal monomers with either lactate orglycolate diol co-linkers, which contain the α-hydroxy carboxylic acidester functionality, for use as vehicles to deliver diflunisal upondegradation. German patents DE 223305 and DE 227999 disclose diglycolicacid-linked salicylic acid. DE 227999 discloses that it can be usedtherapeutically to overcome the stomach-irritating effects of salicylicacid alone while maintaining potency. DE 223305 teaches that thecompounds are useful as medicaments. In addition, Greenwald discloses ingeneral terms the conjugation of its polymer linkers to a drug viaα-hydroxy carboxylic acid ester groups, among others. However, Greenwaldalso teaches that the degradation rate of its prodrugs depends not onlythe type of linking moiety used, but also on whether the polymer linkerpossesses sufficiently high molecular weight.

EMBODIMENTS OF THE INVENTION

An embodiment of the present invention is a compound according toformula (I):

-   -   wherein    -   each D is the same or different and is an active agent, such as        a therapeutic agent,    -   R₁ is selected from the group consisting of        —[(CH₂)_(x)O]_(y)(CH₂)_(z)—, —(CH₂)_(y)—,        —[CH═CH—O]_(y)(CH₂)_(z)—, —[(CH═CH—CH₂—O]_(y)(CH₂)_(z)—,        —[CH₂—CH═CH—O]_(y)(CH₂)_(z)—, —[(CH₂)_(x)O]_(y)(CH═CH)—,        preferably —(CH₂CH₂O)_(y)(CH₂)_(z)— or —(CH₂)—,        -   wherein w is 1 or 2,        -   x is 2 or 3, and        -   y is equal to an integer from 1 to 10, from 1 to 4, or from            1 to 3,        -   z is equal to 1 or 2, and        -   the carbon atoms of R₁ may be optionally substituted with        -   substituents selected from the group consisting of C₁ to C₁₂            alkyl, C₁ to C₁₂ alkoxy, C₃ to C₁₂ cycloalkyl, C₃ to C₁₂            cycloalkoxy, C₁ to C₁₂ alkanoyl, C₁ to C₁₂ alkanoyloxy, C₁            to C₁₂ alkoxy carbonyl, C₁ to C₁₂ alkylthio, azido, cyano,            nitro, fluoro, chloro, bromo, iodo, hydroxy, oxo, carboxy,            aryl, aryloxy, heteroaryl, and heteroaryloxy;    -   each X is the same or different and is selected from the group        consisting of —O—, —NR₂—, —S—, —SO—, and —SO₂—, preferably —O—,        —NR₂—, and —S—, more preferably —O— and —NR₂— and most        preferably —O—,        -   wherein R₂ is an alkyl group of 1 to 12 carbon atoms,            preferably an alkyl group of 1 to 4 carbon atoms or of 1 to            2 carbon atoms, and most preferably a methyl group.

Another embodiment of the present invention is a compound comprising aunit of the formula (II):

-   -   wherein        -   n is a positive integer;        -   p is 0 or 1;        -   each D is the same or different and is an active agent, such            as a therapeutic agent,    -   R₁ is selected from the group consisting of        —[(CH₂)_(x)O]_(y)(CH₂)_(z)—, —(CH₂)_(y)—,        —[CH═CH—O]_(y)(CH₂)_(z)—, —[(CH═CH—CH₂—O]_(y)(CH₂)_(z)—,        —[CH₂—CH═CH—O]_(y)(CH₂)_(z)—, —[(CH₂)_(x)O]_(y)(CH═CH)—,        preferably —(CH₂CH₂O)_(y)(CH₂)_(z)— or —(CH₂)—,        -   wherein w is 1 or 2,        -   x is 2 or 3,        -   y is equal to an integer from 1 to 10, from 1 to 4, or from            1 to 3,        -   z is equal to 1 or 2, and        -   the carbon atoms of R₁ may be optionally substituted with            substituents selected from the group consisting of C₁ to C₁₂            alkyl, C₁ to C₁₂ alkoxy, C₃ to C₁₂ cycloalkyl, C₃ to C₁₂            cycloalkoxy, C₁ to C₁₂ alkanoyl, C₁ to C₁₂ alkanoyloxy, C₁            to C₁₂ alkoxy carbonyl, C₁ to C₁₂ alkylthio, azido, cyano,            nitro, fluoro, chloro, bromo, iodo, hydroxy, oxo, carboxy,            aryl, aryloxy, heteroaryl, and heteroaryloxy;    -   each X is the same or different and is selected from the group        consisting of —O—, —NR₂—, —S—, —SO—, and —SO₂—, preferably —O—,        —NR₂—, and —S—, more preferably —O— and —NR₂— and most        preferably —O—,        -   wherein R₂ is an alkyl group of 1 to 12 carbon atoms,            preferably an alkyl group of 1 to 4 carbon atoms or of 1 to            2 carbon atoms, and most preferably a methyl group provided            that, when p is 0, n is not 1.

Another embodiment of the present invention is a polyanhydridecomprising the compound of formula (II), wherein n is equal to aninteger from 2 to 100 or from 2 to 20.

Another embodiment of the present invention comprises a compound offormula (III):

-   -   wherein        -   n is a positive integer;        -   p is the same or different and is 0 or 1;        -   each D is the same or different and is an active agent, such            as a therapeutic agent,    -   R₁ is the same or different and is selected from the group        consisting of        -   —[(CH₂)_(x)O]_(y)(CH₂)_(z)—, —(CH₂)_(y)—,            —[CH═CH—O]_(y)(CH₂)_(z)—, —[(CH═CH—CH₂—O]_(y)(CH₂)_(z)—,            —[CH₂—CH═CH—O]_(y)(CH₂)_(z)—, —[(CH₂)_(x)O]_(y)(CH═CH)—,            preferably —(CH₂CH₂O)_(y)(CH₂)_(z)— or —(CH₂)—,        -   wherein w is 1 or 2,        -   x is 2 or 3,        -   y is equal to an integer from 1 to 10, from 1 to 4, or from            1 to 3,        -   z is 1 or 2, and        -   the carbon atoms of R₁ may be optionally substituted with            substituents selected from the group consisting of C₁ to C₁₂            alkyl, C₁ to C₁₂ alkoxy, C₃ to C₁₂ cycloalkyl, C₃ to C₁₂            cycloalkoxy, C₁ to C₁₂ alkanoyl, C₁ to C₁₂ alkanoyloxy, C₁            to C₁₂ alkoxy carbonyl, C₁ to C₁₂ alkylthio, azido, cyano,            nitro, halo, hydroxy, oxo, carboxy, aryl, aryloxy,            heteroaryl, and heteroaryloxy;    -   each X is independently selected from the group consisting of        —O—, —NR₂—, —S—, —SO—, and —SO₂—, preferably —O—, —NR₂—, and        —S—, more preferably —O— and —NR₂— and most preferably —O—,        -   wherein R₂ is an alkyl group of 1 to 12 carbon atoms,            preferably an alkyl group of 1 to 4 carbon atoms or of 1 to            2 carbon atoms, and most preferably a methyl group.

Another embodiment of the present invention is a composition comprisingan effective amount of a compound according to the invention, such as offormula (I), (II) and/or (III), and a vehicle. In one embodiment, thecomposition is a pharmaceutical composition comprising a therapeuticallyeffective amount of the compound of the invention and a pharmaceuticallyacceptable vehicle.

Methods of using the inventive compositions, such as therapeutictreatment by administering effective amounts of the composition to amammal in need thereof and industrial applications such as applyingeffective amounts of the composition to a surface where the activity ofthe active agent is desired, are also included in the invention.

Another embodiment of the present invention is a composition for topicaluse such as for acne treatment or bandage coating comprising apharmaceutically acceptable vehicle such as a surfactant and atherapeutically effective amount of a compound having the formula:

DETAILED DESCRIPTION

The compounds and compositions thereof of the invention have desirabledegradation properties under normal conditions of use such that theactive agent in the compound or composition is released at the desiredsite over a suitable period of time. The inventive compounds comprisetwo active agents conjugated to each other by a linker, preferablyattached to them via hydroxyl groups on the active agents such that anester bond is formed between the active agent and linker. The linkersare biocompatible diglycolic acid or polyglycol diacid linkers andderivatives thereof. The rapid elution profiles of these compounds makethem useful, inter alia, in topical applications such as personal careproducts, cosmetics, dressings and wound care and to form or coatdevices, and other uses where it is desired for the active agent to bereleased over a period of time such as within from less than about 1hour to about 48 hours or desirable to have a site specificadministration of the active agent in a composition that is convenientfor administration. Longer release rates can also be achieved. Thepresent invention is also directed to novel oligomers and polymers ofthe compounds of the invention.

As used herein, the term “active agent” is a compound having a usefulactivity, particularly when administered over time and/or administeredtopically to a surface. The useful activity may be for a therapeuticuse, such as for medical treatment of a condition or disorder, or anindustrial use, such as preventing microbial growth in a surface coatingsuch as paint. In one embodiment, the active agent is a therapeuticallyactive compound. By therapeutically active compound is meant a compoundthat upon effective dosage to a mammal can treat, prevent or amelioratesymptoms of a disease or medical condition. Preferred as active agentsare low molecular weight (10000 daltons or less) drugs that havepharmacological activity. Examples of preferred active agents aresalicylic acid and diflunisal. Low molecular weight drugs can also beuseful in industrial applications, such as the application of compoundsof the invention comprising anti-microbial agents to liquid coatings andother liquid formulations to prevent microbial growth. Preferably theactive agent has a molecular weight of 1200 or less, 1000 or less, or900 or less. Examples of suitable active agents are provided below.

As used herein, the active agent or “D” in formulas I, II and III has ahydroxyl group prior to formation of the compounds of the invention. Theactive agent forms an ester bond with a linker through reaction at thehydroxyl group of the active agent with the carboxylic acid group of thelinkers disclosed herein. The active agent also may contain at least onearyl group, preferably a phenyl group, and preferably the activehydroxyl group is attached directly to the aryl group. As used herein,the term “aryl” denotes a phenyl radical or an ortho-fused bicycliccarbocyclic radical having about nine to ten ring atoms in which atleast one ring is aromatic or a heteroaryl. As used herein, the term“heteroaryl” encompasses a radical attached via a ring carbon of amonocyclic aromatic ring containing five or six ring atoms consisting ofcarbon and one to four heteroatoms each selected from the groupconsisting of non-peroxide oxygen, sulfur, and N(X), wherein X is absentor is H, O, C₁ to C₆ alkyl, phenyl or benzyl, as well as a radical of anortho-fused bicyclic heterocycle of about eight to ten ring atomsderived therefrom, particularly a benz-derivative or one derived byfusing a propylene, trimethylene, or tetramethylene diradical thereto.

In the polymers and oligomers of the invention, the active agentcontains a carboxylic acid group in additional to the hydroxyl groupprior to formation of the inventive polymer or oligomer. The activeagent forms a polyanhydride bond with a linker or another active agentthrough reaction of the carboxylic acid on the active agent with acarboxylic acid on the linker or on the other active agent.

The linkers of the present invention are based on diglycolic acid andpolyglycol diacids. The structures of diglycolic acid and polyglycoldiacids are as follows:

In the case of polyglycol diacids, when m equals 1, the polyglycoldiacid is 3,6-dioxaoctanedioic acid (“triglycolic acid”) and when mequals 2, the polyglycol diacid is 3,6,9-trioxaundecanedioic acid. Theselinkers are more hydrophilic in character than their aliphaticequivalents as a result of the incorporation of oxygen into the linkerbackbone. These linkers form α-hydroxy carboxylic acid ester moietieswhen conjugated with active agents containing at least one hydroxylgroup. As used herein, the structure of an α-hydroxy carboxylic acidester moiety is defined as:

wherein R₁ and R₂ are not hydrogen. This combination of featuresincreases the rate of hydrolytic degradation of active agent-linkerconjugates (monomers), oligomers, and polymers containing these linkerswhen compared to such compositions containing aliphatic linkers,resulting in faster release of the active agent.

Use of aliphatic linkers as in the background references discussed abovemay result in an undesirably slow rate of degradation for particularapplications. This is believed to be attributable to their relativehydrophobicity, resulting in a slower rate of hydrolysis of the bondbetween the linker and the active agent. Hydrophilicity of the linkermay be increased by substituting one or more of the carbon atoms of thealiphatic chain of the linker with one or more oxygen atoms. Withoutlimiting the invention in any way, it is believed that the rate ofhydrolysis of these linkers is enhanced due to increased hydrogenbonding capability.

The invention includes compounds of the general structure D-L-D where Dis an active agent and L is a diglycolic acid or polyglycol diacidlinker or derivatives thereof such as the compounds of the formula (I)as defined above. Another embodiment of the present invention is acompound having the formula:

Another embodiment of the present invention is a compound having theformula:

Another embodiment of the present invention is a polyanhydride havingthe formula:

-   -   wherein n is a positive integer greater than 1, such as from 2        to 10, equal to 3 or equal to 4, and wherein R₃ is selected from        the group consisting of —H, —CF₃, —F, —Cl, —Br, —I, —OH, —NH₂,        —NO₂, —CN, C₁ to C₁₂ straight-chain or branched alkyl, C₁ to C₁₂        alkoxy, C₃ to C₁₂ cycloalkyl, C₃ to C₁₂ cycloalkoxy, C₁ to C₁₂        alkanoyl, C₁ to C₁₂ alkanoyloxy, C₁ to C₁₂ alkoxy carbonyl, C₁        to C₁₂ alkylthio, azido, oxo, carboxy, aryl, aryloxy,        heteroaryl, heteroaryloxy, and the following structures:

Another embodiment of the present invention is a polyanhydride havingthe formula:

wherein n is a positive integer greater than 1 and wherein R₃ is

Another embodiment of the present invention is a polyanhydride havingthe formula:

-   -   wherein n is a positive integer greater than 1 such as from 2 to        10, equal to 3 or equal to 4, and R₃ is selected from the group        consisting of —H, —CF₃, —F, —Cl, —Br, —I, —OH, —NH₂, —NO₂, —CN,        C₁ to C₁₂ straight-chain or branched alkyl, C₁ to C₁₂ alkoxy, C₃        to C₁₂ cycloalkyl, C₃ to C₁₂ cycloalkoxy, C₁ to C₁₂ alkanoyl, C₁        to C₁₂ alkanoyloxy, C₁ to C₁₂ alkoxy carbonyl, C₁ to C₁₂        alkylthio, azido, oxo, carboxy, aryl, aryloxy, heteroaryl,        heteroaryloxy, and the following structures:

Another embodiment of the present invention is a polyanhydride havingthe formula:

-   -   wherein n is a positive integer greater than 1 and wherein R₃ is        —H.

Another embodiment of the present invention is a polyanhydride havingthe formula:

wherein n is a positive integer greater than 1 and wherein R₃ is

Another embodiment of the present invention is a polyanhydride of theformula:

wherein n is a positive integer greater than 1.

Another embodiment of the present invention is a polyanhydride of theformula:

wherein n is a positive integer greater than 1.

Another embodiment of the present invention comprises administration ofa composition comprising a therapeutically effective amount of acompound of the invention and a pharmaceutically acceptable vehicle to amammal in need thereof.

A composition of the compound of formula (I) may usually be expected toelute the active agent faster than a polymer of formula (II).

When n of the polyanhydrides comprising a repeating unit is equal to aninteger from 2 to 10, said polyanhydride is properly defined as anoligomer. In the case of the polyanhydride of formula (II) wherein p is0, n is preferably 3 and/or 4. When n of the polyanhydride comprising arepeating unit having the structure of formula (II) is equal to aninteger of 11 or higher, said polyanhydride is properly defined as apolymer. The molecular weight or the value of n is dependent on thedesired properties of the polymer, for example, glass transitiontemperature, elasticity, tackiness, rate of hydration, rate of elution,etc. Preferably, n is an integer less than about 101, more preferably nis an integer less than about 21 and most preferably n is an integerless than about 11.

The compounds of the present invention contain an active agent,preferably a therapeutic agent, substituted with at least one hydroxylgroup and optionally substituted with at least one carboxylic acid groupprior to formation of the compound. Examples of such agents with thesefunctional groups within their structure can be found in almost alltherapeutic classes including, but not limited to, analgesics,anesthetics, anti-acne agents, antibiotics, synthetic antibacterialagents, anti-cancer agents, anticholinergics, anticoagulants,antidyskinetics, antifibrotics, anti-fungal agents, anti-glaucomaagents, anti-infectives, steroidal and non-steroidal anti-inflammatoryagents, anti-neoplastics, anti-osteoporotics, anti-pagetics,anti-Parkinson's agents, anti-psoratics, anti-pyretics,antiseptics/disinfectants, anti-thrombotics, bone resporptioninhibitors, calcium regulators, keratolytics, sclerosing agents andultraviolet screening agents. For preparing the compositions of thepresent invention, the use of therapeutic agents that fall within theclasses of non-steroidal anti-inflammatory agents (NSAIDs),anti-infectives and anti-cancer agents are preferred.

Examples of therapeutic agents containing at least one hydroxyl groupinclude anti-bacterials such as 4-sulfanilamidosalicylic acid,amoxicillin, apalcillin, apicycline, aspoxicillin, biapenem, cefadroxil,cefamandole, cefatrizine, cefbuperazone, cefdinir, cefonicid,cefoperazone, cefpiramide, cefprozil, flomoxef, imipenem, lucensomycin,lymecycline, meropenem, moxalactam, nadifloxacin, panipenem, ritipenem,salazosulfadimidine and sulfaloxic acid. Examples of anti-neoplastictherapeutic agents include carzinophillin A, denopterin, mycophenolicacid, streptonigrin, doxorubicin, paclitaxel, and gemcitabine. Examplesof immunosupressants include mycophenolic acid. Examples of NSAIDsinclude diflunisal, fendosal, gentisic acid, mesalamine, salicylic acid,salsalate and sulfasalazine. The use of NSAIDs is particularlypreferred, with salicylates such as salicylic acid, diflunisal, andsalsalate being more preferred. Most preferred are salicylic acid anddiflunisal.

Salicylates are anti-inflammatory, analgesic, anti-pyretic (feverreducing) and antiseptic compounds having anti-microbial activity. Inparticular, the salicylate salicylic acid is useful for the topicaltreatment and/or control of psoriasis, acne, microbially-derivedmalodor, dandruff, fungus, acne and wart removal. Salicylic acid is alsoknown to be useful in limiting and in reducing scar formation and as akeratolytic agent. Salicylic acid is also used in cosmetic and personalskin care products and works as an exfoliant to reduce skin wrinkles andimprove overall skin appearance of the face, body and scalp.

Other active agents useful in the invention are antioxidants, antisepticagents and antibacterial agents.

The compositions of the invention are also useful for administering acombination of active agents, preferably therapeutic agents, to amammalian host. Such a combination therapy can be carried out in thefollowing ways: 1) a second active, preferably therapeutic, agent can bedispersed within the matrix of a composition of the present invention,and can be released upon degradation of the composition; 2) a secondactive, preferably therapeutic, agent can be appended to a compositionof the present invention (e.g., as a sidechain on the polymer) withbonds that hydrolyze to release the second active, preferablytherapeutic, agent under physiological conditions; 3) the compositionsof the present invention can incorporate two or more different active,preferably therapeutic, agents into their structure (e.g., a polymercomprising one or more units of Formula (I) or a compound of formula(I), (II) or (III) in which D is different); or 4) two compositions ofthe present invention, each with a different active, preferablytherapeutic, agent can be administered together (or within a shortperiod of time). The invention also provides a pharmaceuticalcomposition comprising a composition of the present invention, anotheractive, preferably therapeutic, agent and a pharmaceutically acceptablevehicle.

As they degrade, the compositions of the present invention where theactive, preferably therapeutic, agent is an NSAID do not cause theforeign body response and/or inflammatory response that is associatedwith other biodegradable polymers such as polylactides/glycolides(PLGAs) and polylactides (PLAs). Consequently, when the compositions ofthe present invention are used as a matrix to deliver a secondtherapeutic agent, the NSAIDs are preferred with salicylic acid anddiflunisal being particularly preferred.

The conjugates, oligomers and polymers of the present invention may beanalogously prepared as exemplified in the general synthetic schemes fordiglycolate and triglycolate monomers and polymers below. Furthersynthesis information is provided in U.S. Patent Application2005/0048121 (East et al.).

The compositions of the present invention are particularly suited forlocalized uses, for example, topical application, as a medical device ora coating and they can be formulated as pharmaceutical, personal care,topical or coating compositions. Examples of topical use includepersonal care products, cosmetics and wound care products. For someuses, the compositions can conveniently be formulated as micronizedparticles or as nanoparticles.

Local administration of a pharmaceutical composition of a compound ofthe invention can occur in a wide variety of forms adapted to a chosenroute of administration to a mammal, such as a human patient, e.g.,rectally, parenterally, intravenously, intramuscularly,intraperitoneally, intraspinally (intrathecally), intracranially,topically, ocularly, and subcutaneously.

Therapeutic compositions of the present invention may be administered incombination with a pharmaceutically acceptable vehicle such as an inertdiluent or an assimilable edible carrier. Such compositions andpreparations preferably contain at least 0.1% of the inventive compoundby weight. The percentage of the inventive compounds in preparations maybe varied and may be between about 2% to about 80% of the weight,preferably about 2% to about 60%, of a given unit dosage form. Theamount of therapeutic agent in such compositions is such that aneffective dosage level will be obtained.

For topical use of a salicylic acid composition, generally the amount ofthe therapeutic agent released will range from about 0.5 to about 50weight percent. For acne, (antimicrobial), anti-dandruff, psoriasis andanti-seborrhea, generally the amount of the salicylic acid released isabout 0.5 to 2 percent and for wart removal, corn and callus removalgenerally about 12 to 40 percent when formulated in a plaster, 5 to 17percent when formulated as a colloidion vehicle and about 15 percentwhen formulated as a karaya gum or glycol plaster.

Useful dosages of the inventive compounds can be determined by comparingtheir in vitro activity, and in vivo activity of the therapeutic agentin animal models. Methods for the extrapolation of effective dosages inmice, and other animals, to humans are known to the art; for example,see U.S. Pat. No. 4,938,949. Additionally, useful dosages can bedetermined by measuring the rate of hydrolysis for a given compositionunder various physiological conditions. The amount required for use intreatment will vary not only with the particular composition selectedbut also with the route of administration, the nature of the conditionbeing treated and the age and condition of the mammalian host and willbe ultimately at the discretion of the attendant physician or clinician.

For localized administration, the present compositions can be applied inpure form. For example, the compounds may be applied as particlesadhered to a bandage, gauze pad or other material, or may be formed intoparticles that are used in foot powders. However, it will generally bedesirable to administer them as compositions, in combination with anacceptable vehicle for ease of application. For therapeutic use, thevehicle should be a dermatologically or pharmaceutically acceptablecarrier, which may be a solid or a liquid. Useful solid carriers includefinely divided solids such as talc, clay, microcrystalline cellulose,silica, alumina and the like. Useful liquid carriers include glycols orglycol blends, in which the present compounds can be dissolved ordispersed at effective levels, optionally with the aid of non-toxicsurfactants. Adjuvants such as fragrances and additional anti-microbialagents can be added to optimize the properties for a given use. Theresultant liquid compositions can be applied from absorbent pads, usedto impregnate bandages and other dressings, or sprayed onto the targetarea using pump-type or aerosol sprayers or applied as an ointment,cream or lotion or coated onto wound care products such as dressings,sutures, meshes, etc. Thickeners such as synthetic polymers, fattyacids, fatty acid salts and esters, fatty alcohols, modified cellulosesor modified mineral materials can also be employed with liquid carriersto form spreadable pastes, gels, ointments, soaps, and the like, forapplication directly to the skin of the mammalian host. Examples ofuseful dermatological compositions which can be used to deliver thecompositions of the present invention to the skin are known to the art;for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S.Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman(U.S. Pat. No. 4,820,508).

In another embodiment, the compositions of the present invention will beincorporated into personal care products, such as without limitationcleansing products, conditioning products, antiperspirants, shampoos,deodorants, lotions, creams and cosmetic items. Personal care products,particularly cleansing, conditioning and exfoliation products, havetraditionally been marketed in a variety of forms such as bar soaps,shampoos, creams, lotions, powders and gels. Typically, these productshave attempted to satisfy a number of criteria to be acceptable toconsumers. These criteria include cleansing effectiveness, skin feel,mildness to skin, hair, and ocular mucosae, and lather volume. Idealpersonal cleansers should gently cleanse the skin or hair, cause littleor no irritation, and should not leave the skin or hair with a heavybuildup or overly dry when used frequently. The therapeutic agents inthe conjugates, oligomers and polymers of the invention are releasedafter administration of the personal care product and thereby providethe personal care product with the therapeutic advantage of thetherapeutic agent. For example, by incorporating a compound of theinvention containing as a therapeutic agent salicylic acid into aproduct, sustained delivery of salicylic acid to the skin surface may beobtained, which causes less skin irritation and which may reducemicrobial derived malodor, dandruff, acne, skin wrinkles and/or improveoverall skin appearance.

Because the compositions of the invention contain an active, preferablytherapeutic, agent, the cleansing or conditioning methods also providetherapeutic treatment of the skin or hair according to the therapeuticindications associated with the particular agent that is incorporatedinto the conjugates, oligomers and polymers of the invention. Anotherembodiment of the present invention is a method for treating conditionsof the hair, skin or scalp of a mammal comprising administeringcompositions of the inventive compounds to a mammal.

A personal care product for topical administration such as a cleansingand/or conditioning product for the hair and/or skin preferably containsone or more surfactants. Any suitable surfactant may be used. Thesurfactants of the cleansing component are preferably latheringsurfactants. As used herein, “lathering surfactant” means a surfactant,which when combined with water and mechanically agitated generates afoam or lather. Such surfactants are preferred since increased lather isimportant to consumers as an indication of cleansing effectiveness. Awide variety of lathering surfactants are useful herein and includethose selected from the group consisting of anionic latheringsurfactants, nonionic lathering surfactants, cationic latheringsurfactants, amphoteric lathering surfactants, and mixtures thereof.

Nonlimiting examples of surfactants useful in the compositions of thepresent invention are disclosed in McCutcheon's, Detergents andEmulsifiers, North American edition (1986), published by AlluredPublishing Corporation; McCutcheon's, Functional Materials, NorthAmerican Edition (1992); and U.S. Pat. No. 3,929,678, to Laughlin etal., issued Dec. 30, 1975.

Nonlimiting examples of anionic lathering surfactants include thoseselected from the group consisting of alkyl and alkyl ether sulfates,sulfated monoglycerides, sulfonated olefins, alkyl aryl sulfonates,primary or secondary alkane sulfonates, alkyl sulfosuccinates, acyltaurates, acyl isethionates, alkyl glycerylether sulfonate, sulfonatedmethyl esters, sulfonated fatty acids, alkyl phosphates, acylglutamates, acyl sarcosinates, alkyl sulfoacetates, acylated peptides,alkyl ether carboxylates, acyl lactylates, anionic fluorosurfactants,and combinations thereof. Examples of alkyl ether sulfates which may beused include ammonium, sodium, magnesium, or TEA laureth-3 sulfate.Suitable alkyl sulfosuccinates include disodiumN-octadecylsulfosuccinamate; diammonium lauryl sulfosuccinate;tetrasodium N-(1,2-dicarboxyethyl)-N-octadecylsulfosuccinate; diamylester of sodium sulfosuccinic acid; dihexyl ester of sodiumsulfosuccinic acid; and dioctyl esters of sodium sulfosuccinic acid.Suitable alkyl ether carboxylates include sodium laureth carboxylate.Combinations of anionic surfactants can be used effectively in thepresent invention.

Other anionic materials include the carboxylates, nonlimiting examplesof which include sodium lauroyl carboxylate, sodium cocoyl carboxylate,and ammonium lauroyl carboxylate. Anionic fluorosurfactants can also beused. Other anionic materials include natural soaps derived from thesaponification of vegetable and/or animal fats & oils such as sodiumlaurate, sodium myristate, palmitate, stearate, tallowate, cocoate. Anycounter cation, M, can be used on the anionic surfactant. Preferably,the counter cation is selected from the group consisting of sodium,potassium, ammonium, monoethanolamine, diethanolamine, andtriethanolamine. More preferably, the counter cation is ammonium.

Nonionic lathering surfactants useful herein include those selected fromthe group consisting of alkyl glucosides, alkyl polyglucosides,polyhydroxy fatty acid amides, alkoxylated fatty acid esters, sucroseesters, amine oxides, and mixtures thereof. Commercially availableexamples of these surfactants include decyl polyglucoside (available asAPG 325 CS from Henkel) and lauryl polyglucoside (available as APG 600CSand 625 CS from Henkel). Also useful are sucrose ester surfactants suchas sucrose cocoate and sucrose laurate.

Suitable cationic lathering surfactants include, but are not limited to,fatty amines, di-fatty quaternary amines, tri-fatty quaternary amines,imidazolinium quaternary amines, and combinations thereof. Suitablefatty amines include monoalkyl quaternary amines such ascetyltrimethylammonium bromide. A suitable quaternary amine isdialklamidoethyl hydroxyethylmonium methosulfate.

The term “amphoteric lathering surfactant,” as used herein, is alsointended to encompass zwitterionic surfactants, which are well known toformulators skilled in the art as a subset of amphoteric surfactants. Awide variety of amphoteric lathering surfactants can be used in thecompositions of the present invention. Particularly useful are thosewhich are broadly described as derivatives of aliphatic secondary andtertiary amines, preferably wherein the nitrogen is in a cationic state,in which the aliphatic radicals can be straight or branched chain andwherein one of the radicals contains an ionizable water solubilizinggroup, e.g., carboxy, sulfonate, sulfate, phosphate, or phosphonate.

The compositions of the present invention may contain a variety of othercomponents such as are conventionally used in a given product typeprovided that they do not unacceptably alter the benefits of theinvention. These optional components should be suitable for applicationto human skin and hair, that is, when incorporated into the article theyare suitable for use in contact with human skin without undue toxicity,incompatibility, instability, allergic response, and the like, withinthe scope of sound medical or formulator's judgment. The CTFA CosmeticIngredient Handbook, Second Edition (1992) describes a wide variety ofnon-limiting cosmetic and pharmaceutical ingredients commonly used inthe skin care industry, which are suitable for use in the articles ofthe present invention. Examples of these ingredient classes include:enzymes, abrasives, skin exfoliating agents, absorbents, aestheticcomponents such as fragrances, pigments, colorings/colorants, essentialoils, astringents, etc. (e.g., clove oil, menthol, camphor, eucalyptusoil, eugenol, menthyl lactate, witch hazel distillate), anti-acne agents(e.g., resorcinol, sulfur, salicylic acid, erythromycin, zinc, etc.),anti-caking agents, antifoaming agents, additional antimicrobial agents(e.g., iodopropyl butylcarbamate), antioxidants, binders, biologicaladditives, buffering agents, bulking agents, chelating agents, chemicaladditives, colorants, cosmetic astringents, cosmetic biocides,denaturants, drug astringents, external analgesics, film formers ormaterials, e.g., polymers, for aiding the film-forming properties andsubstantivity of the composition (e.g., copolymer of eicosene and vinylpyrrolidone), humectants, opacifying agents, pH adjusters, propellants,reducing agents, sequestrants, skin bleaching agents (or lighteningagents) (e.g., hydroquinone, kojic acid, ascorbic acid, magnesiumascorbyl phosphate, ascorbyl glucosamine), skin soothing and/or healingagents (e.g., panthenol and derivatives (e.g., ethyl panthenol), aloevera, pantothenic acid and its derivatives, allantoin, bisabolol, anddipotassium glycyrrhizinate), skin treating agents, including agents forpreventing, retarding, arresting, and/or reversing skin wrinkles (e.g.,alpha-hydroxy acids such as lactic acid and glycolic acid andbeta-hydroxy acids such as salicylic acid), thickeners, hydrocolloids,particular zeolites, and vitamins and derivatives thereof (e.g.tocopherol, tocopherol acetate, beta carotene, retinoic acid, retinol,retinoids, retinyl palmitate, niacin, niacinamide, and the like).

Compositions of the compounds of the invention may be used to form orcoat shaped articles, including medical, dental and veterinary devices,such as vascular grafts and stents, bone plates, sutures, wound closingstaples, surgical meshes, dental implants (e.g., dental, oro-maxillary,and alveolar), implantable sensors, implantable drug delivery devices,stents for tissue regeneration, catheters and other articles suitablefor implantation or insertion into a patient. Examples of coatings forshaped articles are disclosed in U.S. Pat. No. 6,486,214; AustralianPatent No. 750,424 B to Uhrich, U.S. App. Pub. No. 20050131199 A1 andU.S. App. Pub. No. 20050048121 A1.

Suitable devices that may be formed from or coated with compositions ofthe compounds of the invention also include stents, e.g., coronaryvascular stents, peripheral vascular stents, urethral stents, biliarystents, stents used for supporting the lumen of other anatomical tubes,and stents used for other medical treatments; catheters, e.g., surgicalcatheters and urinary catheters; grafts; and orthopedic implantsincluding, e.g., hip, knee and shoulder implants, internal and externalfixation devices and spinal cages; drain tubes, endotrachael tubes,intravenous tubes, tampon applicators, tampons, ventilator tubes,endoscopes, arthroscopes, needles, condoms, barrier devices, diagnosticdevices (e.g., speculum), dental appliances, and surgical appliances;balloons, guidewires, wound grafts, meshes, joint prostheses, breastprostheses, fracture management devices, drug dosing devices,pacemakers, mechanical pumps, defibrillators, and filters.

Suitable devices also include commercial devices such as those known inthe art, including without limitation technologies described in: Stuart,M., “Technology Strategies, Stent and Deliver,” Start-Up, Windhover'sReview of Emerging Medical Ventures, pp. 34-38, June 2000); van derGiessen, Willem J., et al. “Marked Inflammatory Sequelae to Implantationof Biodegradable and Nonbiodegradable Polymers in Porcine CoronaryArteries,” Circulation, Vol. 94, No. 7, pp. 1690-1697 (Oct. 1, 1996);Gunn, J. et al., “Stent coatings and local drug delivery,” EuropeanHeart Journal, 20, pp. 1693-1700 (1999).

Compositions of the inventive compounds may be used as an anti-microbialto coat surfaces to inhibit or control mold, bacteria and biofilmgrowth. The compositions may be used to coat surfaces made from variousmaterials, such as wood, metal, plastic (including nylon andpolypropylene), paper, and fabric. The compounds and compositions of theinvention may also be used in or to coat food wrappings, such as with ananti-bacterial or antioxidant active agent. The compounds may contain asactive agents a fungicide, viracidal agent, or a bacteriocidal agent.Such compounds would be useful in industrial applications to preventcontamination and spoilage of a product otherwise susceptible to fungal,viral or bacterial attack.

The compositions of the invention may be applied to a surface by anymeans understood to those skilled in the art, such as by aerosol spray.To inhibit or control mold, bacteria and biofilm growth, the inventivecompounds can be incorporated into paints, stains, coatings and othersurface treatments that can applied to the target surface by brush,roller, spray or any other means that can deliver an effective amount ofsaid compositions. The effect of inhibiting or controlling mold,bacterial and biofilm growth in vinyl construction materials can also beachieved by incorporating the compositions of the invention into suchmaterials, such as vinyl siding, rather than merely applying thecompositions to the surface of the materials.

The practice of the present invention is demonstrated by the Examplesbelow which are not intended to limit the scope of the invention.

EXAMPLES

The following abbreviations are employed throughout the examples: DCM(dichloromethane), DF (diflunisal), SA (salicylic acid), TEA(triethylamine), THF (tetrahydrofuran), TP (triphosgene) and HCl(hydrochloric acid). All solvents and reagents employed in the followingexamples were purchased and used as received. Proton nuclear magneticresonance (¹H NMR) spectra were recorded on a Varian 300 MHz MercuryVX-300 spectrometer using an appropriate deuterated solvent. Chemicalshifts (δ) are reported in parts per million (ppm) downfield fromtetramethylsilane (TMS) and coupling constants (J values) are given inhertz (Hz). Molecular weights (M_(w)) and polydispersity indices (PDI)were determined on a electron light scattering detector (ELSD),miniDAWN, along with a refractive index (RI) detector attached to asingle pump system. Astra software was used for data collection andprocessing. Molecular weights were calibrated relative to a narrowmolecular weight polystyrene standard (Viscotek, Houston, Tex.). TheHPLC impurity profile was performed on an Agilent Rapid Phase C18 column4.6×70 mm column and a different gradients of mobile phase A (0.1% (v/v)TFA in water) and mobile phase B (acetonitrile). A Mettler Toledo pHmeter was used to measure pH using a 3-point calibration (pH 4.00, 7.00and 10.00 standard solutions).

Example 1 Preparation of Bis(2-carboxyphenyl)diglycolate

To a stirred solution of 40.80 g of salicylic acid (0.296 mol) and 24 mLof anhydrous pyridine in 300 mL of anhydrous THF was added 24.8 g ofdiglycolyl chloride (0.145 mol) dissolved in 50 mL of anhydrous THF in aslow, drop-wise fashion. A white precipitate was formed during theaddition. The reaction mixture was stirred at ambient temperature for anadditional 30 minutes. The reaction mixture was poured into 2 L ofice-water containing 25 mL of conc. HCl. After stirring for 15 minutes,the white solid was filtered, and washed with water until the washingswere neutral to pH paper. The product was dried overnight in a vacuumoven at 40° C. After drying, the crude product was twice suspended in300 mL of hexane/ethyl acetate (75:25 v/v), stirred for 30 minutes andfiltered. The product was dried overnight in a vacuum oven at 40° C.Isolated yield was 51 g. ¹H NMR (CDCl₃) δ: 8.05 (dd, 2H, J=1.8 and 7.5Hz), 7.53 (m, 2H), 7.32 (m, 2H), 7.15 (dd, 2H, H=1.8, 7.5 Hz), 6.84 (bs,2H, exchanged with D₂O), 4.63 (s, 4H). ¹³C NMR (DMSO-d₆) δ: 169.2,166.2, 150.3, 134.7, 132.3, 127.2, 124.4, 68.4.

Example 2 Preparation of Bis(2-carboxyphenyl)-3,6-dioxaoctanedioate Step1:

To a suspension of 7.13 g of 3,6-dioxaoctanedioic acid (0.04 mol) in 100mL of anhydrous chloroform was added 10.3 mL of oxalyl chloride (0.12mol) and the mixture was refluxed for 4 hours to give a clear solution.The solution was cooled to room temperature and the volatile componentswere removed in vacuo followed by further drying of the oily residue invacuo to give the product in quantitative yield, which was used in thenext step without further purification.

Step 2:

To a solution of 11.33 g of salicylic acid (0.082 mol) and 7.0 mL ofanhydrous pyridine in 100 mL of anhydrous THF was added the triglycolylchloride from step 1 (0.04 mol) in 50 mL of THF in a slow drop-wisefashion. A white precipitate was formed during the addition. Thereaction mixture was stirred at ambient temperature for another 30minutes and the whole reaction mixture was poured into 1.5 L ofice-water containing 8 mL of concentrated HCl. After stirring for 5minutes, the product was separated as a semi-solid. The product wasextracted into 200 mL of ethyl acetate, washed with 50 mL of water and50 mL of brine solution. The organic layer was dried over 10 g ofanhydrous sodium sulfate and filtered. Solvent was removed and theproduct was dried in vacuo. The oily crude product solidified uponstanding at room temperature. The solid was powdered into fineparticles, twice suspended into 150 mL of hexane-ethyl acetate (75:25v/v), stirred for 30 minutes at room temperature, and filtered. Theproduct was dried overnight in a vacuum oven at 40° C. Isolated yieldwas 8 g. ¹H NMR (CDCl₃) δ: 7.93 (dd, 2H, J=1.8 and 7.5 Hz), 7.64 (m,2H), 7.40 (m, 2H), 7.22 (dd, 2H, J=1.0, 7.9 Hz), 4.42 (s, 4H), 3.74 (s,4H). ¹³C NMR (DMSO-d₆) δ: 169.8, 166.2, 150.4, 134.7, 132.2, 127.1,124.5, 68.5, 41.1.

Comparative Example 1 Preparation of Bis(2-carboxyphenyl) adipate

To a stirred solution of 55.25 g of salicylic acid (0.4 mol) and 200 mLof anhydrous pyridine in 400 mL of anhydrous THF was added 36.6 g ofadipoyl chloride (0.2 mol) dissolved in 100 mL of anhydrous THF in aslow, drop-wise fashion. A white precipitate was formed during theaddition. The reaction mixture was stirred at ambient temperature for anadditional 30 minutes. The reaction mixture was poured into 3 L ofice-water containing 25 mL of concentrated HCl. After stirring for 30minutes, the white solid was filtered and washed with water until thewashings were neutral to pH. The product was dried overnight in a vacuumoven at 40° C. After drying, the crude product was suspended in 300 mLof methanol and the resulting slurry was stirred for 45 minutes atambient temperature and filtered. The product was dried overnight at 40°C. in a vacuum oven. Isolated yield was 75 g. ¹H NMR (DMSO-d₆) δ: 13.08(br s, 2H), 7.91 (dd, 2H, J=8.2, 1.2 Hz), 7.62 (ddd, 2H, J=7.6, 7.6, 1.2Hz), 7.36 (ddd, 2H, J=7.6, 7.6, 1.2 Hz), 7.18 (dd, 2H, 8.2, 1.2 Hz),2.61 (m, 4H), 1.73 (m, 4H). ¹³C NMR (DMSO-d₆) δ: 172.2, 166.4, 150.8,134.4, 132.0, 126.7, 124.5, 124.5, 33.9, 24.2.

Example 3 Preparation of Poly[1,6-bis(2-carboxyphenyl)diglycolate]

To a stirred solution of 6 g of 1,6-bis(2-carboxyphenyl)diglycolate(0.016 mol) in 60 mL of anhydrous DCM was added 5.4 mL of TEA (0.038mol) at 0° C. A solution of 1.7 g of triphosgene in 20 mL of DCM wasadded to the solution in a slow drop-wise fashion. The reaction mixturewas stirred for an additional 30 minutes and then transferred to a 250mL separatory funnel. The solution was washed with 100 mL of 1N HCL, 100mL of water and brine solution. The organic layer was dried over 10 g ofanhydrous magnesium sulfate. The solution was filtered and the solventwas evaporated to a volume of about 30 mL. The polymer solution wasadded to 300 mL of anhydrous pentane with stirring. The precipitatedpolymer was isolated by filtration, and dried in a vacuum oven at 60° C.for 24 hours. Mw=13.6 K; PDI=6.0; ¹H NMR (CDCl₃) δ: 8.10-7.99 (m, 2H),7.71-7.59 (m, 2H), 7.44-7.30 (m, 2H), 7.25-7.16 (m, 2H), 4.54-4.50 (m,4H).

Example 4 Preparation of Poly[1,6-bis(2-carboxyphenyl)diglycolate]

To a stirred solution of 7.41 g of 1,6-bis(2-carboxyphenyl)diglycolate(0.02 mol) in 60 mL of anhydrous DCM was added 5.6 mL of TEA (0.038 mol)at 0° C. A solution of 1.7 g of TP in 20 mL of anhydrous DCM was addedto the solution in a slow drop-wise fashion. The reaction mixture wasstirred for an additional 2 hours and then transferred to a 250 mLseparatory funnel. The solution was washed with 100 mL of 1 N HCl andwith 100 mL of water twice. A white precipitate formed during thewashing was collected by filtration, washed with water, and dried at 50°C. (Example 4A). The organic layer was washed with brine, dried overanhydrous magnesium sulfate, filtered, and the solvent was removed invacuo. The residue was dried at 50° C. in a vacuum oven (Example 4B). ¹HNMR (Example 4A, CDCl₃) δ: 8.12 (dd, J=1.8 & 7.9 Hz), 8.06 (dd, J=1.8 &7.9 Hz), 7.73 (t, J=6.2 Hz), 7.60 (t, J=6.9 Hz), 7.47 (t, J=7.2), 7.35(m), 7.16 (d, J=8.3 hz), 4.65 (s), 4.53 (s). Mw=2.1 K; ¹H NMR (Example4B, CDCl₃) δ: 8.13-8.01 (m), 7.75-7.61 (m), 7.59-7.10 (m), 4.65-4.53(m). Mw=1.6 K.

Comparative Example 2 Preparation of Poly[1,6-bis(2-carboxyphenyl)adipate]

A 250 mL 3-neck flask was charged with 1,6-bis(2-carboxyphenyl) adipate(15.46 g, 0.04 mol.) and 100 mL of anhydrous DCM A slow argon flow wasmaintained in the flask while the reaction mixture was cooled to 0±4° C.TEA (13.94 mL, 0.1 mol.) was added to the reaction flask with stirring.TP (3.96 g) was weighed into a separate flask, dissolved in 25 mL ofanhydrous DCM, and was added to the cooled solution of the monomer in aslow drop-wise fashion. After the addition was complete, the reactionmixture was stirred for another 30 minutes and the polymer solution wastransferred to a 250 mL separatory funnel. The polymer solution waswashed with 1N HCL (100 mL), water (2×100 mL) and aqueous sodiumchloride solution. The organic layer was dried over anhydrous magnesiumsulfate (10.0 g). The solution was filtered into a 250 mL round-bottomflask and then the solvent was removed on a rotary evaporator to reducethe volume to about 80 mL. The polymer solution was added to anhydrousether (800 mL) with stirring. The precipitated polymer was dried in avacuum oven at 40° C. Yield was 11 g. Mw=11.3 K; PDI=1.30; ¹H NMR(CDCl₃) δ: 8.07-8.02 (m, 2H), 7.66-7.60 (m, 2H), 7.36-7.31 (t, 2H,J=7.86 Hz), 7.16 (d, 2H, J=7.92), 2.58 (bs, 4H), 1.72 (bs, 4H).

Example 5 Preparation of 6-Bis[(2-carboxy-4(2′,4′-difluorophenyl)phenyl]glycolate

To a solution of 10.50 g of diflunisal (0.042 mol.) and 3.7 mL ofanhydrous pyridine (0.045 mol.) in 100 mL of anhydrous THF was added3.42 g of diglycolyl chloride (0.02 mol.) in 25 mL of anhydrous THF 1 ina slow drop-wise fashion. A white precipitate was formed during theaddition. The reaction mixture was stirred at ambient temperature for anadditional 30 minutes. The reaction mixture was poured into 1 L ofice-water containing 5 mL of conc. HCl. After stirring for 15 minutes,the white precipitate was filtered and washed with water until thewashings were neutral to pH paper. The product was dried overnight in avacuum oven at 40° C. After drying, the crude product was suspended in100 mL of hexane/ethyl acetate (75:25, v/v) solvent mixture, stirred for30 minutes, and filtered. The product was dried overnight in a vacuumoven at 40° C. Isolated yield was 11 g. ¹H NMR (CDCl₃+DMSO-d₆): 7.96 (d,2H, J=1.3 Hz), 7.48 (dd, 2H, J=6.5 and 1.8 Hz), 7.26-7.02 (m, 2H), 7.0(d, 2H, J=8.2 Hz), 6.80-6.68 (m, 4H), 4.52 (bs, exchanged with D₂O),4.45 (s, 4H)

Example 6 Preparation of1,6-Bis[(2-carboxy-4(2′,4′-difluorophenyl)phenyl)]-3,6-dioxaoctanedioate

The composition was synthesized on a 0.40 mole scale following the sameprocedure used for Example 2. Yield after isolation and purification was19 g. ¹H NMR (CDCl₃+DMSO-d₆): 8.04 (d, 2H, J=1.8 Hz), 7.80 (dd, 2H,J=1.6, 6.5 Hz), 7.68-7.60 (m, 2H), 7.42-7.34 (m, 4H), 7.23-7.17 (m, 2H).

Example 7 Preparation of Poly{1,6-Bis[(2-carboxy-4(2′,4′-difluorophenyl)phenyl]}glycolate

To a cooled, stirred solution of 8.62 g of the diacid of Example 6 (0.15mol.) in 75 mL of anhydrous DCM was added 5.0 mL of TEA. A solution of1.7 g of TP in 20 mL of anhydrous DCM was added to the diacid solutionin a slow drop-wise fashion. The reaction mixture was stirred for anadditional 2 hours and then transferred to a 250 mL separatory funnel.The solution was washed with 50 mL of 1N HCl, 50 mL of water and driedover anhydrous sodium sulfate. The solution was filtered into a 250 mLround bottom flask and the solvent was removed to dryness. Isolatedyield was 7.5 g. Mw=2.6 K; ¹H NMR (CDCl₃): 8.21-8.13 (m), 7.82-7.75 (m),7.48-7.16 (m), 7.02-6.86 (m), 4.74-4.51 (m).

Example 8 Preparation of the Salicylic Acid-Diglycolic AcidLinker-Salicylic Acid-Diglycolic Acid Linker Polymer of Scheme 3

A solution of diglycolyl chloride (3.42 g, 0.02 mol) in anhydrous DCM(50 mL) is added to a solution of DGA bisSA diacid (7.49 g, 0.02 mol,prepared in example 1) and TEA (6.13 mL, 0.044 mol) in anhydrous DCM (30mL) slowly at 0° C. After the completion of the addition, the reactionsolution is stirred for 1 h and diluted with DCM (100 mL). The solutionis washed with 1N HCl (2×150 mL) and distilled water (100 mL), and driedover anhydrous MgSO₄. The solution is concentrated in vacuo to drynessto give the polymer. The polymer is dissolved in anhydrous DCM (100 mL)and TEA (4 equivalents of M_(n) of pre-polymer) is added at 0° C. Asolution of triphosgene in anhydrous DCM is added very slowly to thepolymer solution at 0° C. The addition of triphosgene is continued untilthe target M_(w) is reached by GPC (as monitored by running an aliquotthrough GPC). After the reaction is completed, the mixture is dilutedwith DCM, washed with 1N HCl (2×150 mL) and distilled water (150 mL),and dried over anhydrous MgSO₄. The solution is concentrated in vacuotill a thick oil is obtained and dropped into anhydrous diethyl ether(DCM solution-ether=1:5, v/v) in a Teflon cylinder with stirring toprecipitate the final polymer. The solid is washed further with diethylether and dried in the vacuum oven overnight at 40° C. to give theproduct.

Example 9 Preparation of the Salicylic Acid-Polyglycolic DiacidLinker-Salicylic Acid-Polyglycolic Diacid Linker Polymer of Scheme 4

A solution of triglycolyl chloride (4.30 g, 0.02 mol, prepared inExample 2, step 1) in anhydrous DCM (50 mL) is added to a solution ofTGA bisSA diacid (8.37 g, 0.02 mol, prepared in example 2) and TEA (6.13mL, 0.044 mol) in anhydrous DCM (30 mL) slowly at 0° C. After thecompletion of the addition, the reaction solution is stirred for 1 h anddiluted with DCM (100 mL). The solution is washed with 1N HCl (2×150 mL)and distilled water (100 mL), and dried over anhydrous MgSO₄. Thesolution is concentrated in vacuo to dryness to give the polymer. Thepolymer is dissolved in anhydrous DCM (100 mL) and TEA (4 equivalents ofM_(n) of pre-polymer) is added at 0° C. A solution of triphosgene inanhydrous DCM is added very slowly to the polymer solution at 0° C. Theaddition of triphosgene is continued until the target M_(w) is reachedby GPC (monitored by running an aliquot through GPC). After the reactionis completed, the mixture is diluted with DCM, washed with 1N HCl (2×150mL) and distilled water (150 mL), and dried over anhydrous MgSO₄. Thesolution is concentrated in vacuo till a thick oil is obtained anddropped into anhydrous diethyl ether (DCM solution-ether=1:5, v/v) in aTeflon cylinder with stirring to precipitate the final polymer. Thesolid is washed further with diethyl ether and dried in the vacuum ovenovernight at 40° C. to give the product.

Example 10 Particle Size Determination

Light scattering techniques were employed to assess the particle sizedistributions of samples of the compositions of Examples 1 and 2 andComparative Example 1. Results are shown in Table 1 below:

TABLE 1 Particle Size Distribution Volume Mean Particle Average¹ %Average % Average % Diameter of particles of particles of particlesSample (μm) below 10 μm below 100 μm below 200 μm Comments Example 145.64 11.87 91.69 99.58 Example 2 48.82 37.54 80.89 99.39 Bimodal sizedistribution Comparative 28.85 32.1 96.03 99.99 Example 1 ¹Valuesreflect an average of 3 samples assessed for particle sizeOptimum particle size range for skin deposition is believed to bebetween 1 and 40 microns. Current samples were on average larger thandesired, however, samples did contain a substantial percent of particlesthat fell within the target range.

Example 11 Salicylic Acid Release into Artificial Sweat

Samples of Example 1 and 2 and Comparative Example 1 were placed inartificial sweat or artificial sweat plus proteins and incubated at 35°C. for 3 to 5 minutes, 1, 2, 4, 6 and 24 hours, rapidly filtered (0.22μm filter) and analyzed for salicylic acid by HPLC.

TABLE 2 Salicylic Acid Release (Weight Percent of Maximum Release) Time(hrs) Ex. 1 Ex. 2 Comp. Ex. 1 0.05 20.035 35.25 1.46 1 45.525 47.44 4.932 54.910 44.85 6.03 4 59.795 46.07 6.81 6 54.890 51.20 10.06 24 64.52058.23 26.42Examples 1 and 2 showed rapid initial salicylic acid release rates whileComparative Example 1 exhibited a more moderate salicylic acid releaserate. From these results, Examples 1 and 2 best met the target of 50%salicylic acid release within 24 hours. See FIG. 1 for a graphicalrepresentation of the results in Table 2.

Example 12 Antibacterial Activity

Samples of Examples 1 and 2 and Comparative Example 1 were evaluated intwo different bacterial growth assays. The first test was a standardMinimum Inhibitory Concentration (MIC) assessment involving serialdilution of test compound particle suspensions in water. In this test,the samples were evaluated at 24 hours against human derivedStaphyloccus epidermidis and Corynebacter sp. form organisms. The secondtest utilized a Biosys® system to assess the effect of the samples addedas a dry powder directly to a nutrient broth containing either humanderived Staph epidermidis or a mixed Coryne/Staph milieu. In the case ofthe Biosys test, the bacteria laced nutrient broth alone was used as thenegative control.

Table 3 shows the MIC values obtained for the samples against the targetorganisms; Table 4 shows the Biosys values obtained for the samplesagainst Staphylococcus epidermidis; and Table 5 shows the Biosys valuesobtained for the samples against a mixed Corynebacter/Staph system.

TABLE 3 MIC Values MIC versus Staph MIC versus Coryne epidermidis formTest System mg/ml mg/ml Example 1 ~ 0.2-1 ~ 0.2 Example 2 ~ 2.5 —Comparative >1.67 >1.67 Example 1

Example 1 had the strongest antibacterial activity of the samplestested. Example 2 exhibited modest antibacterial activity against Staph.epi while Comparative Example 1 exhibited little or no antibacterialactivity at the concentrations evaluated.

TABLE 4 Biosys Staph epidermidis Values % Red¹ % Red % Red % Red % RedTest System 50 mg/ml 5 mg/ml 2.5 mg/ml 0.5 mg/ml 0.25 mg/ml Example 1100 100 100 95 10 Example 2 100 100 50 0 0 Comparative 100 100 63 57 0Example 1 ¹% average reduction in bacterial growth rates at 24 hours.

Example 1 provided the strongest antibacterial activity of the samples.

TABLE 5 Biosys Mixed Coryne/Staph Values % Red¹ % Red % Red % Red % RedTest System 50 mg/ml 5 mg/ml 2.5 mg/ml 0.5 mg/ml 0.25 mg/ml Example 1100 100 100 29 66 Example 2 100 100 100 0 5 Comparative 100 100 6 5 0Example 1 ¹% average reduction in bacterial growth rates at 24 hours.

Example 1 provided the strongest antibacterial activity of the samples.The degree of activity of Example 1 is provides an indication ofusefulness in a personal care product.

Example 13

Examples 1, 3 and 4 (both A & B) and Comparative Examples 1 and 2 wereevaluated for rate of release of salicylic acid. Samples were hydrolyzedat 32° C. using acetate buffer (pH 5.5) as relevant condition fortypical skin pH. The materials were placed in 50 mL centrifuge tubes forelution using conventional elution protocols, shaking the tubes in athermostatic environment. Aliquots were taken from the tubes at periodicintervals and immediately placed in a vial and analyzed by HPLC as soonas they were removed from the hydrolysis vessel.

Example 1 hydrolyzed more rapidly than Comparative Example 1.Comparative Example 1 achieves about 90% completion in four days, whileExample 1 is complete in 2.5 hours. The results are illustrated in FIGS.2 (Example 1) and 3 (Comparative Example 1) and indicate an increase inrate of hydrolytic release of therapeutic agent in having the oxygen inthe backbone of the linker, as well as α-alkoxy carboxylic acid estergroups as the moiety that connects the linker to the therapeutic agent.

After three days, Example 3 had achieved only 17% hydrolysis, whileComparative Example 2 had achieved even less. The results for Example 3are illustrated in FIG. 4.

The material of Example 4A had a fast initial elution and then plateauedat 50% completion. The material of Example 4B had a T₁₁₂ of about 18hours. This material was also hydrolyzed using PBS buffer (pH 7.29),which resulted in a faster breakdown and a T₁₁₂ of approximately 5.5hours. The respective salicylic acid release rates of the Example 4A andExample 4B at pH 5.5 and pH 7.29 are compared in FIG. 5. The rates ofExample 4B at pH of 5.5 and 7.29 are compared in FIG. 6.

Significantly slower hydrolysis of the polymers relative to monomerspossibly suggests that it is the effect of higher hydrophobicity of thepolymer resulting in a slower hydration rate. The polymers of Example 3and Comparative Example 2, by being overall more nonpolar, have morehydrophobicity and less access to water for hydrolysis to proceed. Therate of hydrolysis appears to be also dependent on the effect of thecarboxylic acids on the hydrophilicity and polarity relative to the sizeof the molecule. This effect may be reduced as the polymer grows inlength.

These examples are meant to describe and not limit the invention, asmodifications will be apparent to one skilled in the art. Also, all ofthe articles, patent publications and other references referred toherein are expressly incorporated by reference herein in theirentireties.

1. A compound according to formula (I):

wherein each D is the same or different and is an active agent, such asa therapeutic agent, R₁ is selected from the group consisting of—[(CH₂)_(x)O]_(y)(CH₂)_(z)—, —(CH₂)_(y)—, —[CH═CH—O]_(y)(CH₂)_(z)—,—[(CH═CH—CH₂—O]_(y)(CH₂)_(z)—, —[CH₂—CH═CH—O]_(y)(CH₂)_(z)—,—[(CH₂)_(x)O]_(y)(CH═CH)—, wherein w is 1 or 2, x is 2 or 3, and y isequal to an integer from 1 to 10, from 1 to 4, or from 1 to 3, z isequal to 1 or 2, and the carbon atoms of R₁ may be optionallysubstituted with substituents selected from the group consisting of C₁to C₁₂ alkyl, C₁ to C₁₂ alkoxy, C₃ to C₁₂ cycloalkyl, C₃ to C₁₂cycloalkoxy, C₁ to C₁₂ alkanoyl, C₁ to C₁₂ alkanoyloxy, C₁ to C₁₂ alkoxycarbonyl, C₁ to C₁₂ alkylthio, azido, cyano, nitro, fluoro, chloro,bromo, iodo, hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl, andheteroaryloxy; each X is the same or different and is selected from thegroup consisting of —O—, —NR₂—, —S—, —SO—, and —SO₂—, wherein R₂ is analkyl group of 1 to 12 carbon atoms.
 2. The compound of claim 1, whereineach D is independently selected from the group consisting ofanti-inflammatory agents, anti-infective agents, antibacterial agents,antiseptic agents and antioxidants.
 3. The compound of claim 2 havingthe formula:


4. The compound of claim 2 having the formula:


5. A compound comprising a unit of the formula (II):

wherein n is a positive integer; p is 0 or 1; each D is the same ordifferent and is an active agent, such as a therapeutic agent, R₁ isselected from the group consisting of —[(CH₂)_(x)O]_(y)(CH₂)_(z)—,—(CH₂)_(y)—, —[CH═CH—O]_(y)(CH₂)_(z)—, —[(CH═CH—CH₂—O]_(y)(CH₂)_(z)—,—[CH₂—CH═CH—O]_(y)(CH₂)_(z)—, —[(CH₂)_(x)O]_(y)(CH═CH)—, wherein w is 1or 2, x is 2 or 3, y is equal to an integer from 1 to 10, from 1 to 4,or from 1 to 3, z is equal to 1 or 2, and the carbon atoms of R₁ may beoptionally substituted with substituents selected from the groupconsisting of C₁ to C₁₂ alkyl, C₁ to C₁₂ alkoxy, C₃ to C₁₂ cycloalkyl,C₃ to C₁₂ cycloalkoxy, C₁ to C₁₂ alkanoyl, C₁ to C₁₂ alkanoyloxy, C₁ toC₁₂ alkoxy carbonyl, C₁ to C₁₂ alkylthio, azido, cyano, nitro, fluoro,chloro, bromo, iodo, hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl,and heteroaryloxy; each X is the same or different and is selected fromthe group consisting of —O—, —NR₂—, —S—, —SO—, and —SO₂—, wherein R₂ isan alkyl group of 1 to 12 carbon atoms, when p is 0, n is not
 1. 6. Thecompound of claim 5, wherein n is an integer from 2 to
 100. 7. Thecompound of claim 5, wherein the unit of formula (II) comprises

wherein n is a positive integer greater than 1 and wherein R₃ isselected from the group consisting of —H, —CF₃, —F, —Cl, —Br, —I, —OH,—NH₂, —NO₂, —CN, C₁ to C₁₂ straight-chain or branched alkyl, C₁ to C₁₂alkoxy, C₃ to C₁₂ cycloalkyl, C₃ to C₁₂ cycloalkoxy, C₁ to C₁₂ alkanoyl,C₁ to C₁₂ alkanoyloxy, C₁ to C₁₂ alkoxy carbonyl, C₁ to C₁₂ alkylthio,azido, oxo, carboxy, aryl, aryloxy, heteroaryl, heteroaryloxy, and thefollowing structures:


8. The compound of claim 7, wherein R₃ is —H.
 9. The compound of claim7, wherein R₃ is


10. The compound of claim 5, wherein the unit of formula (II) comprises

wherein n is a positive integer greater than 1 and wherein R₃ isselected from the group consisting of —H, —CF₃, —F, —Cl, —Br, —I, —OH,—NH₂, —NO₂, —CN, C₁ to C₁₂ straight-chain or branched alkyl, C₁ to C₁₂alkoxy, C₃ to C₁₂ cycloalkyl, C₃ to C₁₂ cycloalkoxy, C₁ to C₁₂ alkanoyl,C₁ to C₁₂ alkanoyloxy, C₁ to C₁₂ alkoxy carbonyl, C₁ to C₁₂ alkylthio,azido, oxo, carboxy, aryl, aryloxy, heteroaryl, heteroaryloxy, and thefollowing structures:


11. The compound of claim 10, wherein R₃ is —H.
 12. The compound ofclaim 10, wherein R₃ is


13. The compound of claim 8, wherein n is equal to an integer from 2 to10.
 14. The compound of claim 8, wherein n is equal to
 3. 15. Thecompound of claim 5, wherein each D is independently selected from thegroup consisting of anti-inflammatory agents, anti-infective agents,antibacterial agents, antiseptic agents and antioxidants.
 16. Acomposition comprising an effective amount of the compound of claim 1and a suitable vehicle.
 17. A method for treating conditions of thehair, skin or scalp of a mammal comprising administering the compositionof claim 16 to a mammal.
 18. A composition comprising an effectiveamount of the compound of claim 5 and a suitable vehicle.
 19. A methodfor treating conditions of the hair, skin or scalp of a mammalcomprising administering the composition of claim 18 to a mammal.
 20. Atopical composition comprising a surfactant and a therapeuticallyeffective amount of a compound having the formula:


21. A method for treating conditions of the hair, skin or scalp of amammal comprising administering the composition of claim 20 to a mammal.22. A device coated with or comprised of the compound of claim
 1. 23. Amethod for inhibiting mold, bacteria or biofilm formation on a surfacecomprising applying an effective amount of the compound of claim 1 tothe surface or admixing an effective amount of the compound of claim 1with the surface as it is formed.
 24. A device coated with or comprisedof the compound of claim
 5. 25. A method for inhibiting mold, bacteriaor biofilm formation on a surface comprising applying an effectiveamount of the compound of claim 5 to the surface or admixing aneffective amount of the compound of claim 5 with the surface as it isformed.
 26. A polyanhydride comprising a compound of formula (III):

wherein n is a positive integer; p is the same or different and is 0 or1; each D is the same or different and is an active agent, such as atherapeutic agent, R₁ is the same or different and is selected from thegroup consisting of —[(CH₂)_(x)O]_(y)(CH₂)_(z)—, —(CH₂)_(y)—,—[CH═CH—O]_(y)(CH₂)_(z)—, —[(CH═CH—CH₂—O]_(y)(CH₂)_(z)—,—[CH₂—CH═CH—O]_(y)(CH₂)_(z)—, —[(CH₂)_(x)O]_(y)(CH═CH)—, preferably—(CH₂CH₂O)_(y)(CH₂)_(z)— or —(CH₂)— wherein w is 1 or 2, x is 2 or 3, yis equal to an integer from 1 to 10, from 1 to 4, or from 1 to 3, z is 1or 2, and the carbon atoms of R₁ may be optionally substituted withsubstituents selected from the group consisting of C₁ to C₁₂ alkyl, C₁to C₁₂ alkoxy, C₃ to C₁₂ cycloalkyl, C₃ to C₁₂ cycloalkoxy, C₁ to C₁₂alkanoyl, C₁ to C₁₂ alkanoyloxy, C₁ to C₁₂ alkoxy carbonyl, C₁ to C₁₂alkylthio, azido, cyano, nitro, halo, hydroxy, oxo, carboxy, aryl,aryloxy, heteroaryl, and heteroaryloxy; each X is independently selectedfrom the group consisting of —O—, —NR₂—, —S—, —SO—, and —SO₂—, whereinR₂ is an alkyl group of 1 to 12 carbon atoms.
 27. The polyanhydride ofclaim 26 of the formula:

wherein n is a positive integer greater than
 1. 28. The polyanhydride ofclaim 26 of the formula:

wherein n is a positive integer greater than 1.